Pulmonary hypertension (PH) can complicate hypoxia due to chronic obstructive pulmonary disease (COPD), and is associated with increased morbidity and mortality in COPD. Hypoxic PH is associated with pulmonary endothelial dysfunction including decreased nitric oxide (NO) and prostacyclin (PGI2) production, vasoconstriction, and endothelial and vascular smooth muscle cell proliferation. Large-conductance Ca2+- activated potassium channels (BKCa) are expressed in endothelial cells (EC), and open in response to intracellular Ca2+, leading to K+ efflux and membrane hyperpolarization. In ECs, hyperpolarization can cause an increase in intracellular Ca2+ entry leading to the release of vasodilators, such as NO, PGI2 and endothelium-derived hyperpolarizing factor (EDHF); factors which also affect cellular proliferation. There is limited data on the importance of endothelial K+ channels in PH. Hypoxia causes an increase in endothelial BKCa expression, yet a decrease in their activity. The mechanism of increased BKCa expression, yet decreased activity, in hypoxic lung endothelial cells is not known. Also, it is not known whether increasing the endothelial BKCa activity can improve hypoxic pulmonary endothelial dysfunction, vascular remodeling and PH. Our overall hypothesis is that increased endothelial BKCa 1-subunit expression and decreased activity provides a readily available hyperpolarization reserve in hypoxia. Hence, activation of endothelial BKCa will improve endothelial function in hypoxia. SPECIFIC AIMS: Aim 1: We will determine the expression of lung microvascular endothelial BKCa 1- subunit in response to hypoxia and investigate the underlying mechanism. Aim 2: We will determine the activity of lung microvascular endothelial BKCa in response to hypoxia and investigate the underlying mechanism. Aim 3: We will determine the effect of endothelial BKCa activation on endothelial vasodilatory function, EC proliferation and vascular remodeling in response to hypoxia. PUBLIC HEALTH RELEVANCE: Endothelial dysfunction is an important component of pulmonary vascular diseases including pulmonary hypertension (PH) associated with hypoxia, a common disease among Veterans. Pulmonary hypertension can complicate hypoxia due to chronic obstructive pulmonary disease (COPD), and is associated with increased morbidity and mortality in COPD, a significant problem in Veterans. The proposed studies will investigate the role of endothelial BKCa channels in modulating endothelial function in general and specifically in hypoxic settings. Also, the proposed studies will elucidate the potential of endothelial BKCa channel activation as a novel therapeutic target in PH associated with hypoxia and COPD through the improvement of endothelial function in hypoxia.